Dual orexin receptor antagonist induces changes in core body temperature in rats after exercise.

Hypothalamic orexin neurons are involved in various physiological functions, including thermoregulation. The orexinergic system has been considered as a potent mediator of the exercise response. The present study describes how the antagonization of the orexinergic system by a dual orexin receptor antagonist (DORA) modifies the thermoregulatory process during exercise. Core Body Temperature (CBT) and Spontaneous Locomotor Activity (SLA) of 12 male Wistar rats were recorded after either oral administration of DORA (30 mg/kg or 60 mg/kg) or placebo solution, both at rest and in exercise conditions with treadmill running. DORA ingestion decreased SLA for 8 hours (p < 0.001) and CBT for 4 hours (p < 0.01). CBT (°C) response was independent of SLA. The CBT level decreased from the beginning to the end of exercise when orexin receptors were antagonized, with a dose-dependent response (39.09 ± 0.36 and 38.88 ± 0.28 for 30 and 60 mg/kg; p < 0.001) compared to placebo (39.29 ± 0.31; p < 0.001). CBT increased during exercise was also blunted after DORA administration, but without dose effects of DORA. In conclusion, our results favor the role of orexin in the thermoregulation under stress related to exercise conditions.

Novel multitarget-directed ligands (MTDLs) with acetylcholinesterase (AChE) inhibitory and serotonergic subtype 4 receptor (5-HT4R) agonist activities as potential agents against Alzheimer's disease: the design of donecopride.

In this work, we describe the synthesis and in vitro evaluation of a novel series of multitarget-directed ligands (MTDL) displaying both nanomolar dual-binding site (DBS) acetylcholinesterase inhibitory effects and partial 5-HT4R agonist activity, among which donecopride was selected for further in vivo evaluations in mice. The latter displayed procognitive and antiamnesic effects and enhanced sAPPα release, accounting for a potential symptomatic and disease-modifying therapeutic benefit in the treatment of Alzheimer's disease.

Age-dependent effects of chronic fluoxetine treatment on the serotonergic system one week following treatment.

RATIONALE: Selective serotonin reuptake inhibitors (SSRIs) such as fluoxetine are increasingly used for the treatment of depression in children. Limited data are, however, available on their effects on brain development and their efficacy remains debated. Moreover, previous experimental studies are seriously hampered in their clinical relevance. OBJECTIVES: The aim of the present study was to investigate putative age-related effects of a chronic treatment with fluoxetine (5 mg/kg, either orally or i.p. for 3 weeks, 1 week washout) using conventional methods (behavioral testing and binding assay using [(123)I]ß-CIT) and a novel magnetic resonance imaging (MRI) approach. METHODS: Behavior was assessed, as well as serotonin transporter (SERT) availability and function through ex vivo binding assays and in vivo pharmacological MRI (phMRI) with an acute fluoxetine challenge (10 mg/kg oral or 5 mg/kg i.v.) in adolescent and adult rats. RESULTS: Fluoxetine caused an increase in anxiety-like behavior in treated adult, but not adolescent, rats. On the binding assays, we observed increased SERT densities in most cortical brain regions and hypothalamus in adolescent, but not adult, treated rats. Finally, reductions in brain activation were observed with phMRI following treatment, in both adult and adolescent treated animals. CONCLUSION: Collectively, our data indicate that the short-term effects of fluoxetine on the 5-HT system may be age-dependent. These findings could reflect structural and functional rearrangements in the developing brain that do not occur in the matured rat brain. phMRI possibly will be well suited to study this important issue in the pediatric population.